KATP channels are necessary for glucose- dependent increases in amyloid-β and Alzheimer's disease-related pathology

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-beta (A beta) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and A beta pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of A beta, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing A beta pathology in patients with diabetes or prediabetes.

Automated summary

Elevated blood glucose levels can increase brain excitability and A beta release, linking type 2 diabetes and Alzheimer's disease. The KATP channels, which couple energy availability with cellular excitability, play a role in AD pathogenesis. Manipulation of Kir6.2-KATP channels may hold therapeutic promise in reducing A beta pathology in patients with diabetes or prediabetes.